TY - JOUR

T1 - Cryosynthesis of Co-Crystals of Poorly Water-Soluble Pharmaceutical Compounds and Their Solid Dispersions with Polymers. the "meloxicam-Succinic Acid" System as a Case Study

AU - Ogienko, Andrey G.

AU - Myz, Svetlana A.

AU - Ogienko, Anna A.

AU - Nefedov, Andrey A.

AU - Stoporev, Andrey S.

AU - Mel'Gunov, Maxim S.

AU - Yunoshev, Alexander S.

AU - Shakhtshneider, Tatyana P.

AU - Boldyrev, Vladimir V.

AU - Boldyreva, Elena V.

PY - 2018/12/5

Y1 - 2018/12/5

N2 - Co-crystals of pharmaceutical compounds are widely used to improve the properties of drug formulations, such as dissolution behavior, bioavailability, or tabletability. The main methods of their synthesis include co-crystallization from solution, melt, or cogrinding. Only a few examples have been documented when co-crystals have been obtained by freeze-drying, namely, in systems where the components of a target co-crystal had similar aqueous solubilities. This work illustrates the potential of freeze-drying for obtaining pharmaceutical cocrystals when the solubilities of individual components differ drastically. Co-crystals of a model system - meloxicam and succinic acid - could be obtained both as a pure crystalline phase and forming a solid dispersion with a polymeric carrier. We show that even for pharmaceutical compounds with very low aqueous solubility, co-crystals with well-soluble coformers can be successfully produced under well-optimized conditions of cooling and subsequent freeze-drying. The rate of release of meloxicam from the fine solid dispersion of its cocrystal with succinic acid in polyethylenglycol obtained by freeze-drying was significantly higher than dissolution rates of (a) pure meloxicam cocrystals with succinic acid obtained by different variants of freeze-drying (thin film freezing, TFF, and spray freeze-drying, SFD), (b) the powder of meloxicam co-crystal with succinic acid obtained by liquid-assisted cogrinding. The possibility to obtain co-crystals of components with very different aqueous solubilities not only by TFF or SFD techniques but also by freezing solutions in vials at temperatures significantly higher than that of liquid nitrogen is shown.

AB - Co-crystals of pharmaceutical compounds are widely used to improve the properties of drug formulations, such as dissolution behavior, bioavailability, or tabletability. The main methods of their synthesis include co-crystallization from solution, melt, or cogrinding. Only a few examples have been documented when co-crystals have been obtained by freeze-drying, namely, in systems where the components of a target co-crystal had similar aqueous solubilities. This work illustrates the potential of freeze-drying for obtaining pharmaceutical cocrystals when the solubilities of individual components differ drastically. Co-crystals of a model system - meloxicam and succinic acid - could be obtained both as a pure crystalline phase and forming a solid dispersion with a polymeric carrier. We show that even for pharmaceutical compounds with very low aqueous solubility, co-crystals with well-soluble coformers can be successfully produced under well-optimized conditions of cooling and subsequent freeze-drying. The rate of release of meloxicam from the fine solid dispersion of its cocrystal with succinic acid in polyethylenglycol obtained by freeze-drying was significantly higher than dissolution rates of (a) pure meloxicam cocrystals with succinic acid obtained by different variants of freeze-drying (thin film freezing, TFF, and spray freeze-drying, SFD), (b) the powder of meloxicam co-crystal with succinic acid obtained by liquid-assisted cogrinding. The possibility to obtain co-crystals of components with very different aqueous solubilities not only by TFF or SFD techniques but also by freezing solutions in vials at temperatures significantly higher than that of liquid nitrogen is shown.

KW - PHYSICOCHEMICAL PROPERTIES

KW - MECHANOCHEMICAL SYNTHESIS

KW - CARBOXYLIC-ACIDS

KW - PHASE-DIAGRAM

KW - COCRYSTALS

KW - DRUGS

KW - SOLUBILITY

KW - GLYCINE

KW - DESIGN

KW - FROZEN

UR - http://www.scopus.com/inward/record.url?scp=85056595068&partnerID=8YFLogxK

U2 - 10.1021/acs.cgd.8b01070

DO - 10.1021/acs.cgd.8b01070

M3 - Article

AN - SCOPUS:85056595068

VL - 18

SP - 7401

EP - 7409

JO - Crystal Growth and Design

JF - Crystal Growth and Design

SN - 1528-7483

IS - 12

ER -